According to a world-wide estimate from the World Health Organization (WHO) for 2005, at least 400 millions of adults present excess body weight and most of them suffer from pathologies related to this overweight. The WHO estimates that by 2015, 2.3 billions of adults will suffer from overweight and that 700 millions of adults will be obese. Obesity is associated with increased circulating plasma levels of free fatty acids and triglycerides which contribute to insulin resistance in peripheral tissues like skeletal muscle. In obesity, adipose tissues are enlarged and present an altered secretion profile is for hormones, such as adipokines like leptin and adiponectin, playing a role in the control of body weight, insulin sensitivity, inflammation, angiogenesis, and lipid metabolism, as compared to healthy individuals.
It is known that excess body weight, and in particular adiposity, is directly associated with a reduction in insulin sensitivity, generally compensated by a further stimulation of pancreatic insulin secretion to prevent an increase in blood glucose levels. Therefore, increased adiposity, especially in the abdominal region, is known to be a strong risk factor for the development of insulin resistance which may then progress into type 2 diabetes. Increased peripheral insulin resistance, defined as a less effective response of tissues to insulin in terms of glucose uptake and inhibition of hepatic glucose production, leads first to β-cells having an initial attempt to override the increased insulin demand and then results in an alteration in their functional role and a decline in their number, a dysfunction leading to hyperglycaemia and characterizing type 2 diabetes.
Further, obesity is one of the major components of the metabolic syndrome, characterized as a cluster of syndromes including central obesity plus at least two other conditions selected from elevated serum triglycerides, low levels of high density cholesterol (HDL), elevated blood pressure and elevated fasting glucose due to insulin resistance. Metabolic syndrome patients are twice as likely to die from, and three times as likely to have, a heart attack or stroke compared with people without the syndrome. In addition, people with metabolic syndrome have a fivefold greater risk of developing type 2 diabetes. Over 60% of metabolic syndrome patients will progress to type II diabetes, 50% will develop a cardiovascular disease, over 35% will suffer an acute myocardial infarction, and up to 20% will suffer a stroke. It is estimated that around 20-25% of the world's adult population have the metabolic syndrome. Further, obesity is also known to be a strong risk factor for the development of further disorders such as some cancers.
Therefore, there is huge heath and economical needs for the development of new treatments for managing obesity and/or insulin resistance. There is a need as well for the development of treatments for metabolic syndrome as there is currently no treatment is available for this multi-component syndrome and this syndrome is the source of further disorders such as severe cardiovascular and diabetic complications.
Oxytocin (OT) is a neurohypophyseal hormone nonapeptide (Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1)) synthesized both centrally and peripherally and exerting various physiological effects. Within the central nervous system (CNS), the OT gene is expressed in neurons of the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON). The magnocellular OT neurons in these nuclei project to the neurohypophysis and are the major source of systemically released OT, whereas parvocellular OT neurons of the PVN project centrally. OT is synthesized peripherally in several organs, such as the ovary, testis, thymus, kidney and heart. Up to now, a single OT receptor (OTR) was cloned, which is expressed in various tissues, including adipose tissue. In keeping with such a wide distribution in its production and binding sites, OT was demonstrated to be implicated in several central and peripheral processes (Gimpl et al., 2001, Physiol. Rev., 81, 629-683). OT is currently used for stimulation of uterine contraction to induce labor, for the control of post-partum hemorrhage following delivery of placenta and for stimulation of lactation (Pitocin®, Parke-Davis, Morris Plains, N.J. and Syntocinon®, Novartis Pharmaceuticals, East Hanover, N.J.). Administration of OT has been reported to also increase female sexual response and to be beneficial in the treatment of male sexual dysfunction (Pfaus, 2009, J. Sex Med. June, 6, 1506-33).